Morphine provides relief to millions of suffering patients with acute (e.g. post-surgical) and chronic (e.g. cancer and non-cancer pain such as arthritis and musculoskeletal pain). Major issues accompany opiate use including respiratory depression, tolerance, constipation, insomnia, and nausea. Potential drugs to replace opiates or decrease deleterious side effects offer respite for millions of opiate-treated patients. Metabotropic glutamate receptor (mGluR) agonists may be candidate drugs to help these debilitated patients. mGluRs consist of Groups I (mGluR1 &5), II (mGluR2 &3) and III (mGluR4, 6, 7 &8). Group I activates adenylyl cyclase (AC) to increase neuronal activity, but Groups II and III inhibit AC to decrease neuronal activity. Behavior and electrophysiology data show that Group III inhibits pain transmission at the spinal cord level, but it is unknown if Group III agonists directly inhibit peripheral nociceptors. Spinal or systemic administration of Group III agonists potentiates morphine analgesia in nerve injury, but peripheral Group III enhancement of morphine analgesia is unknown. Our lab previously demonstrated expression of mGluR8 by sensory neurons, indicating peripheral relevance of Group III. Preliminary data strongly suggest that Group III activation reduces nociceptor activity in inflamed but not naive. Moreover, sub-analgesic doses of Group III agonist + morphine reduce inflamed peripheral nociceptor responses. Previous studies implicate PKA activation in inflammatory pain, but both Group III and mu opiate receptors (5OR) will suppress neuronal PKA activity. Given this evidence, Group III might potentiate morphine via concomitant suppression of the PKA pathway in peripheral nociceptors, but this is unknown. In the present study we fill these knowledge gaps by investigating peripheral actions and mechanisms of Group III in naove and inflamed states: with or without morphine. We hypothesize that intraplantar (ipl) Group III agonists reduce nociceptive behaviors and nociceptor responses in inflamed but not naove states. Finally, we propose that Group III potentiates morphine analgesia at sub- analgesic concentrations via concomitant suppression of PKA. Using a multifaceted approach (i.e. anatomical, behavior-pharmacological and in vitro electrophysiological studies), we will test the overall hypothesis that Group III activation has an anti-hyperalgesic effect on peripheral nociceptors and can potentiate peripheral morphine-induced analgesia. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to demonstrate the Group III mGluR agonists have an anti-hyperalgesic affect when applied in the periphery. Furthermore, the studies will show that peripheral Group III mGluRs can interact with peripheral mu opiate receptors, decreasing the amount of morphine needed to relieve pain. Thus, peripheral pairing of low dose morphine with a Group III agonist will decrease inflammatory pain as much or more than high dose morphine alone, a clinically important finding that will aid millions of patients who take opiates for acute or chronic pain management.